Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia

Hyperhomocyst(e)inemia is associated with endothelial dysfunction. Mechanis ms responsible for endothelial dysfunction in hyperhomocyst(e)inemia may in volve impaired bioavailability of endothelium-dependent nitric oxide. We te sted the hypothesis that hyperhomocyst(e)inemia is associated with an eleva ted plasma concentration of asymmetric dimethylarginine (ADMA), an endogeno us inhibitor of nitric oxide synthase, One group of adult cynomolgus monkey s was fed either a control or hyperhomocyst(e)inemic diet for 4 weeks in a randomized crossover design. The second group was fed an atherogenic diet t hat produces both hyperhomocyst(e)inemia and hypercholesterolemia for 17 mo nths, followed by an atherogenic diet supplemented with B vitamins for 6 mo nths to decrease plasma homocyst(e)ine concentration. Human endothelial cel ls were used to study the effects of methionine and homocysteine in the pre sence or absence of f3 vitamins or the methylation inhibitor S-adenosylhomo cysteine on the formation of ADMA and its inactive stereoisomer, symmetric dimethylarginine. The hyperhomocyst(e)inemic diet produced 2- to 3-fold inc reases in plasma levels of homocyst(e)ine and ADMA (both P<0.05), The ather ogenic diet also produced elevated plasma levels of homocyst(e)ine and ADMA (both P<0.05). Supplementation of the atherogenic diet with B vitamins dec reased the plasma levels of homocyst(e)ine but did not affect the plasma le vels of ADMA or endothelial function. There was a strong correlation betwee n plasma ADMA and homocyst(e)ine and a strong inverse correlation between A DMA and carotid artery relaxation to acetylcholine. ADMA release by culture d endothelial cells was significantly increased in the presence of methioni ne or homocysteine. This effect was blocked by S-adenosylhomocysteine but n ot by B vitamins. We conclude that plasma levels of ADMA are elevated in hy perhomocyst(e)inemia. Because ADMA acts as a competitive inhibitor of endot helial nitric oxide synthase, these findings suggest a novel mechanism for impaired endothelial function in hyperhomocyst(e)inemia.